Desai Jayesh, Shankar Sridhar, Heinrich Michael C, Fletcher Jonathan A, Fletcher Christopher D, Manola Judi, Morgan Jeffrey A, Corless Christopher L, George Suzanne, Tuncali Kemal, Silverman Stuart G, Van den Abbeele Annick D, van Sonnenberg Eric, Demetri George D
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5398-405. doi: 10.1158/1078-0432.CCR-06-0858.
Resistance to imatinib mesylate is emerging as a clinical challenge in patients with metastatic gastrointestinal stromal tumors (GIST). Novel patterns of progression have been noted in a number of these patients. The objective of this study was to correlate molecular and radiologic patterns of imitinib-refractory disease with existing conventional criteria for disease progression.
Patients with metastatic GIST treated with imatinib were followed with serial computed tomography/magnetic resonance imaging and [(18)F]fluoro-2-deoxy-d-glucose positron emission tomography. Where feasible, biopsies were done to document disease progression.
A total of 89 patients were followed for a median of 43 months. Forty-eight patients developed progressive disease. A unique "resistant clonal nodule" pattern (defined as a new enhancing nodular focus enclosed within a preexisting tumor mass) was seen in 23 of 48 patients and was thought to represent emergence of clones resistant to imatinib. Nodules were demonstrable a median of 5 months (range, 0-13 months) before objective progression defined by tumor size criteria and were the first sign of progression in 18 of 23 patients. Median survival among patients whose first progression was nodular was 35.1 months, compared with 44.6 months for patients whose first progression met Southwest Oncology Group criteria (P = 0.31). Comparative tumor biopsies were done in 10 patients at baseline and from progressing nodules. Genotypic analyses of KIT and PDGFRA kinases were done, revealing new activating kinase mutations in 80% (8 of 10) of these patients.
The resistant clonal nodule is a unique pattern of disease progression seen in patients with GISTs after an initial response to imatinib and reflects the emergence of imatinib-resistant clones. Conventional tumor measurements (Southwest Oncology Group/Response Evaluation Criteria in Solid Tumors) do not detect this subtle finding. A new enhancing nodule growing within a preexisting tumor mass should be classified as a new lesion and be regarded, at least, as partial progression of GIST.
对甲磺酸伊马替尼耐药正成为转移性胃肠道间质瘤（GIST）患者面临的一项临床挑战。在许多此类患者中已注意到新的进展模式。本研究的目的是将伊马替尼难治性疾病的分子和放射学模式与现有的疾病进展传统标准相关联。
对接受伊马替尼治疗的转移性GIST患者进行连续计算机断层扫描/磁共振成像以及[（18）F]氟 - 2 - 脱氧 - D - 葡萄糖正电子发射断层扫描随访。在可行的情况下，进行活检以记录疾病进展。
共对89例患者进行了中位43个月的随访。48例患者出现疾病进展。在48例患者中的23例中观察到一种独特的“耐药克隆结节”模式（定义为存在于先前肿瘤块内的新的强化结节灶），被认为代表对伊马替尼耐药的克隆的出现。结节在根据肿瘤大小标准定义的客观进展前中位5个月（范围0 - 13个月）可被检测到，并且是23例患者中18例的首个进展迹象。首次进展为结节状的患者中位生存期为35.1个月，而首次进展符合西南肿瘤协作组标准的患者为44.6个月（P = 0.31）。对10例患者在基线和进展结节处进行了对比肿瘤活检。对KIT和PDGFRA激酶进行了基因分型分析，在这些患者中的80%（10例中的8例）发现了新的激活激酶突变。
耐药克隆结节是GIST患者在对伊马替尼初始反应后出现的一种独特的疾病进展模式，反映了伊马替尼耐药克隆的出现。传统的肿瘤测量（西南肿瘤协作组/实体瘤疗效评价标准）未检测到这一细微发现。在先前存在的肿瘤块内生长的新的强化结节应被分类为新病变，并且至少应被视为GIST的部分进展。
